Indium(III) chloride-sodium borohydride system: a convenient radical reagent for an alternative to tributyltin hydride system

The indium hydride generated from NaBH4 and InCl3, is a promising candidate of alternative to Bu3SnH. In particular, the catalytic performance of InCl3 in the dehalogenation of alkyl and aryl halides, intramolecular cyclization and intermolecular coupling reaction are noteworthy.     

Triethylsilane-indium(III) chloride system as a radical reagent

[reaction: see text] A novel generation method of indium hydride (Cl2InH) was found by the transmetalation of InCl3 with Et3SiH. In the intramolecular cyclization of enynes, the previously reported system (NaBH4-InCl3) has a problem of side reactions with the coexistent borane. In contrast, the problem was solved by the presented system, which affords effective hydroindation of alkynes.     

Switching the reactivity of dihydrothiopyran-4-one with aldehydes by aqueous organocatalysis: Baylis-Hillman, aldol, or aldol condensation reactions

An aqueous medium containing catalytic amounts of a tertiary amine was employed to direct the chemoselectivity of the reaction of aldehydes with 1a. With DBU, 2 was formed at room temperature as a rare exemplary of Baylis-Hillman reactions in heterocyclic enones. DABCO alternated the pathway toward an aldol reaction to form syn/anti mixtures of 3 with the syn isomers being the major products. With Et(3)N, aldol condensation dominated.     

Reductive cross-aldol reaction using bromoaldehyde and an aldehyde mediated by germanium(II): one-pot, large-scale protocol

[reaction: see text] The reaction of alpha-bromoaldehyde with aldehyde in the presence of GeCl(2)-dioxane gave the syn-selective cross-aldol equivalent. A catalytic amount of Bu(4)NBr improved the yield and selectivity. The initially formed aldol adduct (beta-germoxyaldehyde) did not suffer from over-reaction. This system enabled an intramolecular aldol reaction to give cyclic compounds effectively. One-pot synthetic methodology including bromination of aldehyde followed by cross-aldol reaction with the second aldehyde was successful on a large-scale.     

Unexpected formation of stannolanes and trigonal bipyramidal tin complexes by radical cyclization reaction

Optically active stannolanes and trigonal bipyramidal pentacoordinated tin complexes were readily prepared by radical cyclization of N-propargylated chiral aza-Morita-Baylis-Hillman adducts induced by Bu(3)SnH. A translocated radical through the cyclization attacked the Bu(3)Sn group in an S(H)2 manner.     

Highly chemoselective reductive amination of carbonyl compounds promoted by InCl3/Et3SiH/MeOH system

A new strategy has been developed for reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH system, which is a nontoxic system with highly chemoselective and nonwater sensitive properties. The methodology can be applied to a variety of cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are found to be stable under our conditions. The reaction shows a first-order kinetics profile with respect to both InCl3 and Et3SiH. Spectroscopic techniques such as NMR and ESI-MS have been employed to probe the active and resulting species arising from InCl3 and Et3SiH in MeOH, which are important in deriving a mechanistic proposal. In the ESI-MS studies, we have first discovered the existence of stable methanol-coordinated indium(III) species which are presumably responsible for the gentle generation of indium hydride at room temperature. The solvent attribution was crucial in tuning the reactivity of [In-H] species, leading to the establishment of mild reaction conditions. The system is superior in flexible tuning of hydride reactivity, resulting in the system being highly chemoselective.     

Mechanistic insight into hydrosilylation reactions catalyzed by high valent ReX (X = O, NAr, or N) complexes: the silane (Si-H) does not add across the metal-ligand multiple bond

Treatment of oxo and imido-rhenium(V) complexes Re(X)Cl3(PR3)2 (X = O, NAr, and R = Ph or Cy) (1-2) with Et3SiH affords Re(X)Cl2(H)(PR3)2 in high yields. Cycloaddition of silane across the ReX multiple bonds is not observed. Two rhenium(V) hydrides (X = O and R = Ph, 4a; X = NMes and R = Ph, 5a) have been structurally characterized by X-ray diffraction. The kinetics of the reaction of Re(O)Cl3(PPh3)2 (1a) with Et3SiH is characterized by phosphine inhibition and saturation in [Et3SiH]. Hence, formation of Re(O)Cl2(H)(PPh3)2 (4a) proceeds via a sigma-adduct followed by heterolytic cleavage of the Si-H bond and transfer of silylium (Et3Si+) to chloride. Oxo and imido complexes of rhenium(V) (1-2) as well as their nitrido analogues, Re(N)Cl2(PR3)2 (3), catalyze the hydrosilylation of PhCHO under ambient conditions, with the reactivity order imido > oxo > nitrido. The isolable oxorhenium(V) hydride 4a reacts with PhCHO to afford the alkoxide Re(O)Cl2(OCH2Ph)(PPh3)2 (6a) with kinetic dependencies that are consistent with aldehyde coordination followed by aldehyde insertion into the Re-H bond. The latter (6a) regenerates the rhenium hydride upon reaction with Et3SiH. These stoichiometric reactions furnish a possible catalytic cycle. However, quantitative kinetic analysis of the individual stoichiometric steps and their comparison to steady-state kinetics of the catalytic reaction reveal that the observed intermediates do not account for the predominant catalytic pathway. Furthermore, for Re(O)Cl2(H)(PCy3)2 and Re(NMes)Cl2(H)(PPh3)2 aldehyde insertion into the Re-H bond is not observed. Therefore, based on the kinetic dependencies under catalytic conditions, a consensus catalytic pathway is put forth in which silane is activated via sigma-adduct formation cis to the ReX bond followed by heterolytic cleavage at the electrophilic rhenium center. The findings presented here demonstrate the so-called Halpern axiom, the observation of "likely" intermediates in a catalytic cycle, generally, signals a nonproductive pathway.     

Metal-catalyzed reduction of HCONR'2, R' = Me (DMF), Et (DEF), by silanes to produce R'2NMe and disiloxanes: a mechanism unraveled

We demonstrate that using Mo(CO)(6), Mo(CO)(5)NMe(3), and (η(5)-C(5)H(5))Mn(CO)(3) as catalysts for the silane, R(3)SiH, reduction of N,N-dimethylformamide (DMF), and N,N-diethylformamide (DEF), we can observe, intercept, and isolate, the important siloxymethylamine intermediates, R(3)SiOCH(2)NR'(2), R' = Me, Et, for the first time. In the presence of excess DMF such intermediates thermally react with a variety of silanes to form the corresponding disiloxanes in the absence of a metal catalyst. We also show that the germanium hydrides, Et(3)GeH and Bu(3)GeH, also reduce DMF to form trimethylamine and the corresponding digermoxane but observe no intermediates R(3)GeOCH(2)NMe(2). Bu(3)SnH reduces DMF, but along with the low yields of Bu(3)SnOSnBu(3) (but no Bu(3)SnOCH(2)NMe(2)) significant side products are obtained including (Bu(3)Sn)(2) and Bu(4)Sn. In the absence of DMF the siloxymethylamines can undergo metal-catalyzed reactions with silanes, germanes and stannanes to form disiloxanes, and R(3)SiOER(3) E = Ge, Sn, respectively. To date, the most efficient catalyst for this latter process is (η(5)-C(5)H(5))Mo(CO)(3)CH(3) via a photochemical reaction.     

Studies toward the synthesis of alpha-fluorinated phosphonates via tin-mediated cleavage of alpha-fluoro-alpha-(pyrimidin-2-ylsulfonyl)alkylphosphonates. Intramolecular cyclization of the alpha-phosphonyl radicals

Treatment of the alpha carbanions generated from several alpha-(pyrimidin-2-ylsulfonyl)alkylphosphonates with Selectfluor gave high yields of the alpha-fluoro-alpha-(pyrimidin-2-ylsulfonyl)alkylphoshonates, which were desulfonylated [Bu(3)SnH/2,2'-azobisisobutyronitrile (AIBN)/benzene or toluene/Delta] to give alpha-fluoroalkylphosphonates. "Catalytic" tin hydride, generated from tributyltin chloride and excess polymethylhydrosiloxane in the presence of potassium fluoride, also effected removal of the pi-deficient alpha-(pyrimidin-2-ylsulfonyl) group from the phosphonate esters. Substitution of Bu(3)SnD for Bu(3)SnH gave access to alpha-deuterium-labeled phosphonates. Prolonged treatment of alpha-(pyridin-2-ylsulfonyl)alkylphosphonate with excess Bu(3)SnH/AIBN or catalytic tin hydride also effected desulfonylation but in moderate yields. This represents a mild new methodology for removal of the synthetically useful pi-deficient heterocyclic sulfone moiety and an alternative route for the preparation of alpha-fluorinated phosphonates. Desulfonylation is suggested to proceed via attack of tin radical at an oxygen (or sulfur) atom of the sulfonyl group to give a stabilized alpha-phosphonyl radical intermediate. The latter was found to undergo 5-exo-trig ring closure to give the corresponding 2-methylcyclopentylphosphonates. Treatment of diethyl 1-bromohex-6-enylphosphonate with Bu(3)SnH/AIBN produced an analogous mixture of ring-closure products. Treatment of [(2-bromo-5- methoxyphenyl)(fluoro)(pyrimidin-2-ylsulfonyl)]methylphosphonate with Bu(3)SnH resulted in an intramolecular radical [1,5]-ipso substitution reaction and migration of the pyrimidinyl ring to give fluoro[5-methoxy-2-(pyrimidin-2-yl)phenyl]methylphosphonate.     

Facile synthesis of coumarin bioisosteres—1,2-benzoxathiine 2,2-dioxides

A simple and reproducible procedure for the synthesis of bioisosteres of coumarin—1,2-benzoxathiine 2,2-dioxide is presented. The developed method is based on the intramolecular aldol cyclization of derivatives of mesylsalicyl aldehydes in the presence of strong organic bases, where best results were obtained with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It has been shown that depending on the nature of the substituent in the aromatic ring, intermediate aldol adducts (3,4-dihydro-1,2-benzoxathiin-4-ol 2,2-dioxides) in different ratios with title compound are formed. Dehydration of the intermediate aldols with POCl₃ led to full conversion into 1,2-benzoxathiine 2,2-dioxide derivatives. The scaffold of 1,2-benzoxathiine 2,2-dioxide is unequivocally proven by a single-crystal X-ray structure.     

α-Carbonyl Radical Cyclizatio n in Organic Synthesis

Intramolecular radical cyclization reactions are now used routinely to synthesize carbocyclic and heterocyclic structures. We have reported that α-carbonyl radicals 1, generated from the corresponding iodo ketones or enones, underwent intramolecular radical cyclization smoothly to afford products 2.1, 2,3     

Cyclizations of N-stannylaminyl radicals onto nitriles

[reaction: see text] Stannylaminyl radicals derived from radical reactions of Bu(3)SnH with azidoalkylmalononitriles exhibit highly efficient 5- and 6-exo cyclization onto either nitrile group to give aminoiminyl radicals that in turn are reduced to amidines or undergo successive 5-exo cyclization onto an internal alkene.     

Regulated-stereoselective construction of thirteen stereogenic centers necessary for the frame of (+)-discodermolide, based on iterative Lewis acid-promoted aldol reactions

The segments C(1)-C(13) and C(15)-C(21) containing the 13 stereogenic centers required for the frame of (+)-discodermolide were synthesized in good to excellent enantio- and diastereoselectivities from a common racemic aldehyde, derived from 2-methyl-1,3-propanediol. The enantioselective aldol reactions of the racemic aldehyde with a silylketene acetal, derived from ethyl 2-bromopropionate, in the presence of chiral oxazaborolidinones, prepared in situ with N-p-toluenesulfonyl-(R)- and -(S)-valine and BH(3).THF, proceeded under kinetic control to give the stereotriads with a high degree of enantioselectivity. Enantioselective (chiral borane) and diastereoselective (BF(3).OEt(2) and TiCl(4)) aldol reactions with the silylketene acetal, coupled with diastereoselective radical debrominations (Bu(3)SnH, Et(3)B, with or without MgBr(2)), were used iteratively. This aldol reaction strategy for the construction of the polypropionate frame dramatically shortened the steps needed for the construction of the final segments.     

Boron-mediated aldol reaction of carboxylic esters: complementary anti- and syn-selective asymmetric aldol reactions

The boron-mediated aldol reaction of carboxylic esters is described in detail. Contrary to the general belief that carboxylic esters are inert under the condition of the boron enolate formation, propionate esters are enolized with certain combinations of a boron triflate and an amine. More importantly, the stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with c-Hex2BOTf and triethylamine produces anti-aldol products, and that with Bu2BOTf and diisopropylethylamine gives syn-aldol products selectively after reaction with aldehydes. Complementary anti- and syn-selective asymmetric aldol reactions with structurally related, readily available chiral norephedrine-derived propionate esters are developed.     

Efficient and regioselective 9-endo cyclization of α-carbamoyl radicals

With the promotion of Lewis acid BF(3)?OEt(2), various N-(hex-5-enyl)-2-iodoalkanamides underwent efficient and regioselective 9-endo iodine-atom-transfer radical cyclization reactions at room temperature. The cyclized products were readily converted to the corresponding azonan-2-ones by reduction with Bu(3)SnH or to hexahydroindolizin-3(5H)-ones by treatment with aqueous Na(2)CO(3) in a one-pot, two-stage manner.     

A practical one-pot synthesis of vinylstannanes from ketones

Treatment of ketones with Bu3SnLi followed by addition of MsCl/Et3N to the resulting alkoxide provides vinylstannanes. Cyclic vinylstannanes are particularly amenable to this procedure and isolated yields of 81-83% could be consistently attained. Traces of Bu3SnH in crude reaction products could be removed by stirring in CHCl3 with a catalytic amount of AIBN followed by filtration through silica gel.     

Asymmetric synthesis of alpha-amino acids based on carbon radical addition to glyoxylic oxime ether

The first asymmetric synthesis of alpha-amino acids based on diastereoselective carbon radical addition to glyoxylic imine derivatives is reported. The addition of an isopropyl radical, generated from i-PrI, Bu(3)SnH, and Et(3)B in CH(2)Cl(2) at 25 degrees C, to achiral glyoxylic oxime ether 1 proceeded regioselectively at the imino carbon atom of the oxime ether group to give an excellent yield of the C-isopropylated product 2. The competitive reaction using glyoxylic oxime ether 1 and aldoxime ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals was enhanced by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl radical addition to glyoxylic oxime ether 1 proceeded smoothly even at -78 degrees C, in contrast to the unactivated aldoxime ether 4. A high degree of stereocontrol in the carbon radical addition to the glyoxylic oxime ether was achieved by using Oppolzer's camphorsultam as a chiral auxiliary. The stannyl radical-mediated reaction of the camphorsultam derivative 6 with an isopropyl radical at -78 degrees C afforded a 96:4 diastereomeric mixture, 7a, of the C-isopropylated product. The reductive removal of the benzyloxy group of the major diastereomer (R)-7a, by treatment with Mo(CO)(6) and the subsequent removal of the sultam auxiliary by standard hydrolysis, afforded the enantiomerically pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new methodology, a variety of alkyl radicals were employed in the addition reaction which gave the alkylated products 7 with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural alpha-amino acids. Even in the absence of Bu(3)SnH, treatment of 6 with alkyl iodide and Et(3)B at 20 degrees C gave the C-alkylated products 7 with moderate diastereoselectivities. The use of Et(2)Zn as a radical initiator, instead of Et(3)B, was also effective for the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2, 2'-isopropylidenebis(4-phenyl-2-oxazoline) and MgBr(2) gave excellent chemical yield of the valine derivative 2 in 52% ee.     

Theoretical study of intramolecular aldol condensation of 1, 6-diketones: trimethylsilyl substituent effect

Diastereoselective intramolecular aldol condensations are investigated in an experimental and computational study of 1, 6-diketones. Ab initio results show the importance of the acid medium and disapprove the possibility of a spontaneous cyclization, even for silylated compounds. The combination of both experimental and computational approaches brings valuable information on the mechanism and on the selectivity of the aldol reaction. It is found that the enolization of the diketone is a key step in acid-catalyzed mechanism. The cyclization step bears a very small activation energy. The dehydration of the aldols are discussed.     

Tributylgermanium hydride as a replacement for tributyltin hydride in radical reactions

Tributylgermanium hydride (Bu(3)GeH) can be used as an alternative to tributyltin hydride (Bu(3)SnH) as a radical generating reagent with a wide range of radical substrates. Tributylgermanium hydride has several practical advantages over tributyltin hydride, e.g. low toxicity, good stability and much easier work-up of reactions. The reagent can be easily prepared in good yield and stored indefinitely. Suitable substrates include iodides, bromides, activated chlorides, phenyl selenides, tert-nitroalkanes, thiocarbonylimidazolides and Barton esters. Alkyl, vinyl and aryl radicals can be generated in radical reactions including reduction and cyclisation processes. Common radical initiators such as ACCN and triethylborane can be used. The slower rate of hydrogen abstraction by carbon-centred radicals from Bu(3)GeH as compared to Bu(3)SnH facilitates improved cyclisation yields. Polarity reversal catalysis (PRC) with phenylthiol can be used in reactions which generate stable radical intermediates which will not abstract hydrogen from Bu(3)GeH.     

Carbocyclization by radical closure onto O-trityl oximes: dramatic effect of diphenyl diselenide

O-Trityl oximes of 5- and 6-iodoaldehydes undergo radical cyclization to produce oximes when treated in refluxing tetrahydrofuran (THF) with Bu3SnH, 1,1'-azobis(cyclohexanecarbonitrile), i-Pr2NEt, and diphenyl diselenide (PhSeSePh).